bims-ovdlit 2023-01-08 papers

Br J Cancer. 2023 Jan 02.

Prognostic relevance of HRDness gene expression signature in ovarian high-grade serous carcinoma; JGOG3025-TR2 study.

Shiro Takamatsu, Kosuke Yoshihara, Tsukasa Baba, Muneaki Shimada, Hiroshi Yoshida, Hiroaki Kajiyama, Katsutoshi Oda, Masaki Mandai, Aikou Okamoto, Takayuki Enomoto, Noriomi Matsumura.

BACKGROUND: This study aimed to evaluate the homologous recombination repair pathway deficiency (HRD) in ovarian high-grade serous carcinoma (HGSC).
METHODS: In the ovarian cancer data from The Cancer Genome Atlas, we identified genes differentially expressed between tumours with and without HRD genomic scars and named these genes "HRDness signature". We performed SNP array, RNA sequencing, and methylation array analyses on 274 HGSC tumours for which targeted sequencing of 51 genes and clinical data were available to generate JGOG3025-TR2 dataset. The HRDness signature was tested on external datasets, including the JGOG3025-TR2 cohort, by computational scoring and machine-learning prediction.
RESULTS: High scores and positive predictions of the HRDness signature were significantly associated with BRCA alterations, genomic scar scores, and better survival. On the other hand, among cases with high scores and/or positive predictions, those with BRCA1 methylation showed poorer survival. In the JGOG3025-TR2 cohort, HRD status was significantly associated with the use of olaparib after relapse and progression-free survival after its initiation.
CONCLUSIONS: The HRDness gene expression signature is associated with a good prognosis, while BRCA1 methylation is associated with a poor prognosis. The newly generated JGOG3025-TR2 dataset will be useful in future HGSC studies.

DOI: https://doi.org/10.1038/s41416-022-02122-9

Clin Cancer Res. 2023 Jan 03. pii: CCR-22-2032. [Epub ahead of print]

Influence of Genomic Landscape on Cancer Immunotherapy for Newly Diagnosed Ovarian Cancer: Biomarker Analyses from the IMagyn050 Randomized Clinical Trial.

PURPOSE: To explore whether patients with BRCA1/2-mutated or homologous recombination-deficient (HRD) ovarian cancers benefitted from atezolizumab in the phase III IMagyn050 (NCT03038100) trial.
METHODS: Patients with newly diagnosed ovarian cancer were randomized to either atezolizumab or placebo with standard chemotherapy and bevacizumab. PD-L1 status of tumor-infiltrating immune cells was determined centrally (VENTANA SP142 assay). Genomic alterations, including deleterious BRCA1/2 alterations, genomic loss of heterozygosity (gLOH), tumor mutation burden (TMB), and microsatellite instability (MSI), were evaluated using the FoundationOne assay. HRD was defined as gLOH ≥16%, regardless of BRCA1/2 mutation status. Potential associations between progression-free survival (PFS) and genomic biomarkers were evaluated using standard correlation analyses and log-rank of Kaplan-Meier estimates.
RESULTS: Among biomarker-evaluable samples, 22% (234/1050) harbored BRCA1/2 mutations and 46% (446/980) were HRD. Median TMB was low irrespective of BRCA1/2 or HRD. Only 3% (29/1024) had TMB ≥10 mut/Mb and 0.3% (3/1022) were MSI-high. PFS was better in BRCA2-mutated versus BRCA2-non-mutated tumors and in HRD versus proficient tumors. PD-L1 positivity (≥1% expression on immune cells) was associated with HRD but not BRCA1/2 mutations. PFS was not improved by adding atezolizumab in BRCA2-mutated or HRD tumors; there was a trend toward enhanced PFS with atezolizumab in BRCA1-mutated tumors.
CONCLUSIONS: Most ovarian tumors have low TMB despite BRCA1/2 mutations or HRD. Neither BRCA1/2 mutation nor HRD predicted enhanced benefit from atezolizumab. This is the first randomized double-blind trial in ovarian cancer demonstrating that genomic instability triggered by BRCA1/2 mutation or HRD is not associated with improved sensitivity to immune checkpoint inhibitors.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-2032

Neoplasia. 2022 Dec 29. pii: S1476-5586(22)00091-4. [Epub ahead of print]36 100866

PAX8 modulates the tumor microenvironment of high grade serous ovarian cancer through changes in the secretome.

Amrita Salvi, Laura R Hardy, Kimberly N Heath, Samantha Watry, Melissa R Pergande, Stephanie M Cologna, Joanna E Burdette.

High grade serous ovarian cancer (HGSC) arises from the fimbriated end of the fallopian tube epithelium (FTE), and in some cases, the ovarian surface epithelium (OSE). PAX8 is a commonly used biomarker for HGSC and is expressed in ∼90% of HGSC. Although the OSE does not express PAX8, murine models of HGSC derived from the OSE acquire PAX8, suggesting that it is not only a marker of Müllerian origin, but also an essential part of cancer progression, potentially from both the OSE and FTE. Previously, we have shown that PAX8 loss in HGSC cells causes tumor cell death and reduces cell migration and invasion. Herein, secretome analysis was performed in PAX8 deleted cells and we identified a reduction of the extracellular matrix (ECM) components, collagen and fibronectin. Immunoblotting and immunofluorescence in PAX8 deleted HGSC cells further validated the results from the secretome analysis. PAX8 loss reduced the amount of secreted TGFbeta, a cytokine that plays a crucial role in remodelling the tumor microenvironment. Furthermore, PAX8 loss reduced the integrity of 3D spheroids and caused a reduction of ECM proteins fibronectin and collagen in 3D cultures. Due to the ubiquitous nature of PAX8 in HGSC, regardless of cell origin, and the association of its reduced expression with decreasing tumor burden, a PAX8 inhibitor could be a promising drug target against various types of HGSC. To accomplish this, we generated a murine oviductal epithelial (MOE) cell line stably expressing PAX8 promoter-luciferase. Using this cell line, we performed a screening assay with a library of FDA-approved drugs (Prestwick Library) and quantitatively assessed these compounds for their inhibition of PAX8. We identified two hits: losartan and captropril, both inhibitors of the renin-angiotensin pathway that inhibit PAX8 expression and function. Overall, this study validates PAX8 as a regulator of ECM deposition in the tumor microenvironment.

Keywords: Fibronectin; Ovarian cancer; PAX8; Tumor microenvironment; Tumor spheroids

DOI: https://doi.org/10.1016/j.neo.2022.100866

Nat Commun. 2023 Jan 05. 14(1): 77

Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis.

Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with germline TP53 pathogenic variants. Here, we perform whole-genome sequence (WGS) analysis of tumors from 22 patients with TP53 germline pathogenic variants. We observe somatic mutations affecting Wnt, PI3K/AKT signaling, epigenetic modifiers and homologous recombination genes as well as mutational signatures associated with prior chemotherapy. We identify near-ubiquitous early loss of heterozygosity of TP53, with gain of the mutant allele. This occurs earlier in these tumors compared to tumors with somatic TP53 mutations, suggesting the timing of this mark may distinguish germline from somatic TP53 mutations. Phylogenetic trees of tumor evolution, reconstructed from bulk and multi-region WGS, reveal that LFS tumors exhibit comparatively limited heterogeneity. Overall, our study delineates early copy number gains of mutant TP53 as a characteristic mutational process in LFS tumorigenesis, likely arising years prior to tumor diagnosis.

DOI: https://doi.org/10.1038/s41467-022-35727-y

Nat Rev Clin Oncol. 2023 Jan 04.

Targeted biopsy reduces detection of clinically insignificant cancer.

Diana Romero.

DOI: https://doi.org/10.1038/s41571-022-00726-x

Physiol Res. 2022 Dec 27. 71(Suppl 1): S151-S159

Functional Morphology of the Human Uterine Tubes in the 21st Century: Anatomical Novelties and Their Possible Clinical Applications.

I Varga, M Csöbönyeiová, K Csöbönyeiová, J Záhumenský, L Pavlíková, C Feitscherová, M Klein.

The uterine tube (UT) pathologies account for 25-35% of female factor infertility. Although these peculiar organs were first studied several hundred years ago, they have become overlooked and neglected mainly due to the successes of reproductive medicine. Nevertheless, the reproductive medicine still faces many challenges regarding the fertility outcomes of in vitro fertilization (IVF). Many obstacles and problems can be resolved by a more detailed understanding of the UT morphology and function during normal reproduction. Over the course of the 21st century, many new insights have been obtained: the presence of a population of telocytes in the tubal wall responsible for normal motility and hormone sensory function, the demonstration of lymphatic lacunae of the mucosal folds necessary for oocyte capture and tubal fluid recirculation, or a thorough profiling of the immune makeup of the UT epithelial lining with the discovery of regulatory T cells presumably important for maternal tolerance towards the semi-allogenic embryo. New discoveries also include the notion that the UT epithelium is male sex hormone-sensitive, and that the UT is not sterile, but harbors a complex microbiome. The UT epithelial cells were also shown to be the cells-of-origin of high-grade serous ovarian carcinomas. Finally, yet importantly, several modern morphological directions have been emerging recently, including cell culture, development of tubal organoids, in silico modelling, tissue engineering and regenerative medicine. All these novel insights and new approaches can contribute to better clinical practice and successful pregnancy outcomes.